Abstract
In the light of the promising bioactivity of the tetraarsenic marine metabolite arsenicin A, the dimethyl analogue 2 and four isomeric methylene homologues (including the natural product itself) were obtained using a one-pot microwave-assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR technique in the structural elucidation of these molecules, they were fully characterized by mass spectrometry and infrared (IR)-spectroscopy, comparing density functional theory (DFT) simulated and experimental spectra. This synthetic procedure provided a fast and efficient access to the cytotoxicity evaluation of organoarsenical leads of the natural hit molecule. From in vitro screening, each tested compound resulted in being more active than the FDA-approved arsenic trioxide, with the most lipophilic molecule in the series showing the best growth inhibition of both leukemia and solid tumor cell lines. These results may open promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors.
Highlights
Arsenic is a paradoxical element, on one hand it is a highly toxic and a notorious carcinogen while on the other it can be a charming medicine
The model compound 9,10-dimethyl-2,4,6,8tetraoxa-1,3,5,7,tetraarsa-tricyclo[3.3.1.13,7]decane (2, Fig. 2) was obtained by heating at 160 °C, As2O3, K2CO3 and propionic acid in propionic anhydride according to procedure previously outlined by Keppler and coworkers, who confirmed the structure by X-ray diffraction analysis[14]
This one-pot method applied to the proper carboxylic acid/anhydride pair was recognized as an attractive procedure for the synthesis of a series of arsenicin A-like molecules
Summary
Arsenic is a paradoxical element, on one hand it is a highly toxic and a notorious carcinogen while on the other it can be a charming medicine. Similar activity was seen for arsenolite (As4O6), which showed apoptosis-inducing effects against human leukemic and some solid tumor cells[2]. These positive results prompted significant interest in the use of arsenic oxides for the treatment of solid tumors. Marine metabolites have gained significant attention as interesting leads, employing their peculiar molecular structures and their natural role in protecting the source organism. In this framework, the marine product arsenicin A (=1,2,4,6-trioxa-1,3,5,7-tetrarsa-tricyclo [3.3.1.13,7] decane), isolated in a small amount from the phloecilosclerid sponge Echinochalina bargibanti collected along the New Caledonian coasts, is an example. In a cytotoxicity evaluation on some human carcinoma cell lines[12, 13], it proved to be very efficient in inducing cell death in acute promyelocytic leukemia cell lines and in stopping the advancement of pancreatic adenocarcinoma and glioblastoma[13]
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